Urethral Reconstruction in Aging Male Patients.

OBJECTIVE: To report stricture characteristics, complications, and treatment outcomes among elderly men undergoing urethral reconstruction. MATERIALS AND METHODS: A retrospective review of urethroplasty cases and outcomes by a single surgeon from 2007 to 2014 was performed. Men were stratified by decade of life at time of surgery (<50, 50-59, 60-69, ≥70 years). Individuals with a history of hypospadias were excluded. RESULTS: Among 514 urethroplasty procedures, 184 (36%) were evaluated in men ≥60 years. When stratified by decade of life, elderly men were more likely to have a history of radiation therapy (0% vs 5% vs 19% vs 50%; P <.0001) and experience treatment failure (6% vs 16% vs 20% vs 26%; P <.0001) during follow-up (median 63 months). The estimated 60-month stricture recurrence-free survival decreased with increasing age at time of urethroplasty (94% vs 89% vs 78% vs 74%; P <.0001). In patients ≥60 years, success rates of anastomotic, substitution, and urethrostomy techniques were 80%, 65%, and 88%; anastomotic urethroplasty success improved after excluding those patients with prior radiation. After surgery, elderly were more likely to have voiding dysfunction and <90-day Clavien ≥3 complications requiring endoscopic intervention. On multivariable analysis, advancing age per decade beyond 50 years was independently associated with risk of urethroplasty failure-50-59 (hazard ratio [HR] 2.39; P = .02), 60-69 (HR 2.80; P = .009), and ≥70 (HR 3.43; P = .003). CONCLUSION: Urethroplasty is safe and effective in the majority of elderly men. Early reconstructive intervention with anastomotic urethroplasty or urethrostomy techniques may optimize outcomes. Voiding dysfunction and prostatic obstruction are common in this population and should be pursued as clinically indicated.

Characteristics of Idiopathic Urethral Strictures: A Link to Remote Perineal Trauma?

OBJECTIVE: To characterize the physical features and reconstructive outcomes of a series of idiopathic urethral strictures (IUS) in an effort to elucidate the nature of this common yet poorly understood entity. PATIENTS AND METHODS: We retrospectively reviewed our urethroplasty database to identify men undergoing initial urethral reconstruction from 2007 to 2014 at 1 of 3 hospitals (N = 514). Patients were stratified by stricture etiology, including IUS, acute trauma, iatrogenic, hypospadias, balanitis xerotica obliterans, and radiation. IUS that had a known history of subacute or repetitive blunt force to the perineum (horseback riding, avid cycling, motocross, etc.) were subclassified as subacute or repetitive perineal trauma (SRPT). RESULTS: Among 466 men undergoing initial reconstruction with available data, 215 (46%) were IUS cases. The median delay between IUS diagnosis and urethroplasty was 5.2 years, during which time men underwent a median of 2 endoscopic treatments. A total of 51 (24%) IUS cases recalled a distinct history of SRPT. Men with SRPT were slightly younger (median 43 vs 48 years, P = .01) but were remarkably similar in terms of urethral stricture length (2 vs 2 cm, P = .15), location (bulbar 96% vs 89%, P = .41), and treatment success (92% vs 88%; P = .61). Bulbar (-)SRPT and (+)SRPT IUS had similar clinical and morphometric features as those with known acute bulbar trauma with excellent 24-month stricture recurrence-free survival rates (93% vs 92% vs 97%, P = .19). CONCLUSION: IUS have clinical features suggesting that many may be related to unrecognized or repetitive perineal trauma. Although treatment tends to be delayed, IUS have excellent urethroplasty success because most are short bulbar strictures amenable to anastomotic urethroplasty.

Homogeneous datasets of triple negative breast cancers enable the identification of novel prognostic and predictive signatures.

BACKGROUND: Current prognostic gene signatures for breast cancer mainly reflect proliferation status and have limited value in triple-negative (TNBC) cancers. The identification of prognostic signatures from TNBC cohorts was limited in the past due to small sample sizes. METHODOLOGY/PRINCIPAL FINDINGS: We assembled all currently publically available TNBC gene expression datasets generated on Affymetrix gene chips. Inter-laboratory variation was minimized by filtering methods for both samples and genes. Supervised analysis was performed to identify prognostic signatures from 394 cases which were subsequently tested on an independent validation cohort (n = 261 cases). CONCLUSIONS/SIGNIFICANCE: Using two distinct false discovery rate thresholds, 25% and <3.5%, a larger (n = 264 probesets) and a smaller (n = 26 probesets) prognostic gene sets were identified and used as prognostic predictors. Most of these genes were positively associated with poor prognosis and correlated to metagenes for inflammation and angiogenesis. No correlation to other previously published prognostic signatures (recurrence score, genomic grade index, 70-gene signature, wound response signature, 7-gene immune response module, stroma derived prognostic predictor, and a medullary like signature) was observed. In multivariate analyses in the validation cohort the two signatures showed hazard ratios of 4.03 (95% confidence interval [CI] 1.71-9.48; P = 0.001) and 4.08 (95% CI 1.79-9.28; P = 0.001), respectively. The 10-year event-free survival was 70% for the good risk and 20% for the high risk group. The 26-gene signatures had modest predictive value (AUC = 0.588) to predict response to neoadjuvant chemotherapy, however, the combination of a B-cell metagene with the prognostic signatures increased its response predictive value. We identified a 264-gene prognostic signature for TNBC which is unrelated to previously known prognostic signatures.

Prognostic and therapeutic implications of distinct kinase expression patterns in different subtypes of breast cancer.

Different kinases are expressed in different clinical subsets of breast cancer. In this study, we assessed kinase expression patterns in different clinical subtypes of breast cancer, evaluated the prognostic and predictive values of kinase metagenes, and investigated their functions in vitro. Four hundred twenty-eight protein kinases in gene expression data were examined from 684 cases of breast cancer and 51 breast cancer cell lines to identify kinase expression patterns. We tested the prognostic value of kinase metagenes in 684 node-negative patients who received no adjuvant therapy and the predictive value in 233 patients who received uniform neoadjuvant chemotherapy. Twelve kinases were overexpressed in estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, 7 in HER2(+), and 28 in ER(-)/HER2(-) cancers, respectively. We examined the functional role of 22 kinases overexpressed in ER(-)/HER2(-) cancers using siRNA. Downregulation of these kinases caused significant subtype-specific inhibition of cell growth in vitro. Two robust kinase clusters, including an immune kinase cluster and a mitosis kinase cluster, were present in all clinical subgroups. High mitosis kinase score was associated with worse prognosis but higher pathologic complete response (pCR) in ER(+)/HER2(-) cancers, but not in ER(-)/HER2(-) or HER2(+) cancers, in univariate and multivariate analyses including other genomic predictors (MammaPrint, genomic grade index, and the 76-gene signature). Conversely, higher immune kinase score was associated with better survival in ER(+)/HER2(-) and HER2(+) tumors and also predicted higher probability of pCR in HER2(+) cancers. Taken together, our results indicate that kinases regulating mitosis and immune functions convey distinct prognostic information that varies by clinical subtype.

Amplification of fibroblast growth factor receptor-1 in breast cancer and the effects of brivanib alaninate.

Fibroblast growth factor receptor-1 (FGFR-1) is amplified in 10% of human breast cancers. The goal of this study was to test the correlation between FGFR-1 amplification and expression and sensitivity to brivanib, an FGFR-1 small molecule inhibitor, in breast cancer cell lines in vitro. Using CGH array and gene expression profiling, FGFR-1 DNA copy number, mRNA, and protein expression were measured in 21 cell lines and correlated with growth inhibition by brivanib. We examined FGFR-1 autophosphorylation and kinase activity, as well as phosphorylation of downstream signaling molecules in response to bFGF and brivanib exposure. CAMA, MDA-MB-361, and HCC38 cells had FGFR-1 amplification and protein overexpression. Brivanib GI(50) values were significantly lower in the gene amplified (15.17 µM, n = 3) compared to normal copy number (69.09 µM, n = 11) or FGFR-1 deleted (76.14 µM, n = 7) cells (P = 0.0107). Among nonamplified cells, there was no correlation between FGFR-1 mRNA or protein expression levels and brivanib sensitivity. Two of three FGFR-1 amplified cells were sensitive to bFGF-induced growth stimulation, which was blocked by brivanib. In cells with amplified FGFR-1, brivanib decreased receptor autophosphorylation, inhibited bFGF-induced tyrosine kinase activity, and reduced phosphorylation of ERK and AKT. Breast cancer cell lines with FGFR-1 gene amplification and protein overexpression are more sensitive to growth inhibition by brivanib than nonamplified cells. These findings suggest that FGFR-1 amplification or protein overexpression in breast cancers may be an indicator for brivanib treatment, where it may have direct anti-proliferative effects in addition to its' anti-angiogenic effects.